Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal of all human malignancies and is responsible for hundreds of thousands of deaths each year. Thus, there is an urgent need to improve our understanding of the molecular underpinnings that drive PDAC initiation, progression and metastasis and to leverage that understanding toward better therapeutic options. The current model proposes that a series of genetic alterations results in a stepwise progression through increasingly dysplastic precursor lesions, or pancreatic intraepithelial neoplasias (PanINs), toward invasive and finally metastatic PDAC. Initiating events identified in early PanIN lesions (PanIN I) include mutations and/or amplification in the KRAS oncogene and the loss of CDKN2A (p16INK4A) tumor suppressor gene, present in >90% and >50% of PDAC/PanINs, respectively (Ryan et al., 2014). Higher grade lesions (PanIN III) and invasive PDAC may accumulate additional genetic lesions, including inactivation of TP53 and TGFβ pathway components (SMAD4, TGFβR1, and TGFβR2), found in 60-70% and 50% of PDAC, respectively (Ryan et al., 2014). However, this fundamental model of PDAC pathogenesis, which is recapitulated in genetically engineered mice, has failed to identify either critical pathways that may be effectively targeted in the clinic or relevant molecular subsets for improved prognosis and stratification of patients toward a more effective therapy.
In addition to the above well-characterized genetic aberrations, it is becoming increasingly apparent that the dysregulation of epigenetic modifiers is central to the initiation and progression of human PDAC as well as many other tumors. Genomic deletions, mutations, and rearrangements recurrently targeting genes encoding components of the SWitch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARC4), have been recently identified in at least 10-15% of PDAC cases. Additionally, mutations in the histone methyltransferase mixed-lineage leukemia protein 2 & 3 (MLL2 & MLL3) and the histone demethylase Kdm6a have been identified in 5-10% of PDAC (Ryan et al., 2014). However, since these chromatin-modifying enzymes may simultaneously regulate the transcription of thousands of genes by altering chromatin structure throughout the genome or may be involved in other cellular functions such as DNA repair and replication, the mechanisms by which these proteins control tumorigenesis have been difficult to elucidate. Specifically, whether these enzymes regulate an individual target gene or set of genes to drive survival, proliferation, cellular transformation, metabolic adaptations or invasive functions in PDAC is unknown; yet this understanding is critical to our ability to leverage data from the molecular profiling of human tumors to identify new therapeutic opportunities in molecularly-defined subsets of disease.